6-43519820-T-A

Position:

• chr6-43519820-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_203290.4(POLR1C):​c.364T>A​(p.Phe122Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLR1C NM_203290.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.89

Genes affected

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749
• PP5: Variant 6-43519820-T-A is Pathogenic according to our data. Variant chr6-43519820-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548465.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR1C	NM_203290.4	c.364T>A	p.Phe122Ile	missense_variant	4/9	ENST00000642195.1
POLR1C	NM_001318876.2	c.364T>A	p.Phe122Ile	missense_variant	4/11
POLR1C	NM_001363658.2	c.364T>A	p.Phe122Ile	missense_variant	4/10
POLR1C	XM_047419577.1	c.364T>A	p.Phe122Ile	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1C	ENST00000642195.1	c.364T>A	p.Phe122Ile	missense_variant	4/9		NM_203290.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypomyelinating leukodystrophy 11 Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

Treacher Collins syndrome 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;D;.;D;.;.;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;.;.;D;D;.;D;T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.4	.;.;M;.;M;.;M;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.1	D;.;D;D;.;.;D;.;.;.
REVEL	Pathogenic	0.66
Sift	Benign	0.049	D;.;D;D;.;.;D;.;.;.
Sift4G	Benign	0.11	T;.;T;T;.;.;T;.;.;.
Polyphen		1.0	.;.;D;.;D;.;D;.;D;.
Vest4		0.78, 0.78, 0.80
MutPred		0.54		.;.;Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);
MVP		0.90
MPC		0.49
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554131502; hg19: chr6-43487558;